ABSTRACT Compulsive eating behavior, an underlying transdiagnostic construct of eating disorders and some forms of obesity, affects an estimated 15 million adults in the United States. Negative reinforcement, or performing a behavior (i.e. overeating) to alleviate a negative emotional state, is conceptualized as a key construct of compulsive eating as well as compulsive drug use. Diminished reward sensitivity is thought to contribute to the negative emotional state driving the negative reinforcing effects of palatable food, but causal neurobiological mechanisms are poorly understood. Recent evidence indicates a key role of the corticotropin releasing factor (CRF) system in the ventral tegmental area (VTA) in downregulation of dopamine systems in animal models of addiction, and this brain stress system is upregulated in the VTA by drugs of abuse. Additionally, the upregulation of the CRF-CRF1 system in the VTA is implicated in driving drug self-administration, escalation of intake, and relapse. In a model of compulsive eating, we have shown that intermittent palatable diet access results in decreased reward sensitivity, increased oral intake of d-Amphetamine, and increased CRF in the VTA. The primary objective of this application is to uncover functional reward circuitry adaptations induced by palatable diet cycling that contribute to reward deficits, compulsive eating, and susceptibility to drug taking. We hypothesize that palatable diet cycling causes reward deficits through a CRF-dependent mechanism in the VTA, where recruited CRF dampens dopaminergic release. A secondary objective is to compare male and female rats on palatable diet cycling induced reward deficits, subsequent susceptibility to drug self- administration, and modulation of these effects by the CRF system. Thus, in Aim 1, we will examine reward system functioning in male and female palatable diet cycled rats, by measuring sensitivity to the reward enhancing effects of d-Amphetamine using intra-cranial self-stimulation (ICSS) procedures. To then determine susceptibility to self-administer drugs of abuse, we will investigate intravenous (IV) d-Amphetamine self- administration, a more reliable method of drug self-administration in animals that avoids the confound of oral ingestion. In Aim 2, we will use viral-mediated CRF-1 receptor gene knockdown in the VTA of TH-Cre rats to examine the role of the CRF-CRF1 system on overconsumption of palatable food in the first hour of renewed access, d-Amphetamine-evoked dopamine release (in vivo microdialysis), reward system functioning (ICSS), and IV drug self-administration. The goal of these experiments is uncovering functional reward circuitry adaptations induced by palatable diet cycling that contribute to reward deficits and addictive-like behaviors. These proposed experiments have potential to unravel the mechanisms linking the brain reward and stress systems in compulsive eating and other addictions with implications for pharmacotherapeutic treatments.